Signal-transducing adaptor protein-2 modulates T-cell functions

Immune responses are orchestrated by controlling the initiation, magnitude, and duration of various signaling pathways. Adaptor proteins act as positive or negative regulators by targeting critical molecules of signaling cascades. Signal-transducing adaptor protein-2 (STAP-2) contains typical features of adaptor proteins, like a pleckstrin homology (PH) domain in the N-terminal region and a Src homology 2 (SH2) domain in the central region. STAP-2 binds to a variety of signaling or transcriptional molecules to control multiple steps of inflammatory/immune responses. STAP-2 enhances T-cell receptor (TCR)-mediated signaling via the association with TCR-proximal CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) and lymphocyte-specific protein tyrosine kinase (Lck). STAP-2 decreases adherence of T-cells to fibronectin (FN) through an association with focal adhesion kinase (Fak) and Casitas B-lineage Lymphoma (c-Cbl), and increases chemotaxis of T-cells toward stromal cell-derived factor-1α (SDF-1α) through interactions with Vav1 and Ras-related C3 botulinum toxin substrate 1 (Rac1). STAP-2 positively regulates activation-induced cell deathrough the association with Fas and caspase-8. This review describes the current knowledge of the roles of STAP-2 in T-cell-dependent immune responses and the possible clinical utility of STAP-2-targeting therapies

Signal-transducing adaptor protein-2 modulates T-cell functions

Immune responses are orchestrated by controlling the initiation, magnitude, and duration of various signaling pathways. Adaptor proteins act as positive or negative regulators by targeting critical molecules of signaling cascades. Signal-transducing adaptor protein-2 (STAP-2) contains typical features of adaptor proteins, like a pleckstrin homology (PH) domain in the N-terminal region and a Src homology 2 (SH2) domain in the central region. STAP-2 binds to a variety of signaling or transcriptional molecules to control multiple steps of inflammatory/immune responses. STAP-2 enhances T-cell receptor (TCR)-mediated signaling via the association with TCR-proximal CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) and lymphocyte-specific protein tyrosine kinase (Lck). STAP-2 decreases adherence of T-cells to fibronectin (FN) through an association with focal adhesion kinase (Fak) and Casitas B-lineage Lymphoma (c-Cbl), and increases chemotaxis of T-cells toward stromal cell-derived factor-1α (SDF-1α) through interactions with Vav1 and Ras-related C3 botulinum toxin substrate 1 (Rac1). STAP-2 positively regulates activation-induced cell deathrough the association with Fas and caspase-8. This review describes the current knowledge of the roles of STAP-2 in T-cell-dependent immune responses and the possible clinical utility of STAP-2-targeting therapies

Propolis suppresses cytokine production in activated basophils and basophil-mediated skin and intestinal allergic inflammation in mice

Background Propolis is a resinous mixture produced by honey bees that contains cinnamic acid derivatives and flavonoids. Although propolis has been reported to inhibit mast cell functions and mast cell-dependent allergic responses, the effect of propolis on basophil biology remains unknown. This study aimed to investigate the inhibitory effect of propolis on FcεRI-mediated basophil activation. Methods To determine the inhibitory effect of propolis on basophil activation in vitro, cytokine production and FcεRI signal transduction were analyzed by ELISA and western blotting, respectively. To investigate the inhibitory effect of propolis in vivo, IgE-CAI and a food allergy mouse model were employed. Results Propolis treatment resulted in the suppression of IgE/antigen-induced production of IL-4, IL-6 and IL-13 in basophils. Phosphorylation of FcεRI signaling molecules Lyn, Akt and ERK was inhibited in basophils treated with propolis. While propolis did not affect the basophil population in the treated mice, propolis did inhibit IgE-CAI. Finally, ovalbumin-induced intestinal anaphylaxis, which involves basophils and basophil-derived IL-4, was attenuated in mice prophylactically treated with propolis. Conclusions Taken together, these results demonstrate the ability of propolis to suppress IgE-dependent basophil activation and basophil-dependent allergic inflammation. Therefore, prophylactic treatment with propolis may be useful for protection against food allergic reactions in sensitive individuals

Signal-transducing adaptor protein-2 has a nonredundant role for IL-33-triggered mast cell activation

Signal-transducing adaptor protein (STAP)-2 is one of the STAP family adaptor proteins and ubiquitously expressed in a variety types of cells. Although STAP-2 is required for modification of Fc epsilon RI signal transduction in mast cells, other involvement of STAP-2 in mast cell functions is unknown, yet. In the present study, we mainly investigated functional roles of STAP-2 in IL-33-induced mast cell activation. In STAP-2-deficient, but not STAP-1-deficient, mast cells, IL-33-induced IL-6 and TNF-alpha production was significantly decreased compared with that of wild-type mast cells. In addition, STAP-2-deficiency greatly reduced TLR4-mediated mast cell activation and cytokine production. For the mechanisms, STAP-2 directly binds to IKK alpha after IL-33 stimulation, leading to elevated NF-kappa B activity. In conclusion, STAP-2, but not STAP-1, participates in IL-33-induced mast cells activation

Pivotal Role of Signal-Transducing Adaptor Protein-2 in Pathogenesis of Autoimmune Hepatitis

Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein involved in inflammatory and immune responses, such as inflammatory bowel disease and allergic responses. In this study, we investigated the role of STAP-2 in the pathogenesis of autoimmune hepatitis. After intravenous injection of concanavalin A (ConA), STAP-2 knock out (KO) mice showed more severe liver necrosis along with substantial lymphocyte infiltration compared to wild type (WT) mice. Serum alanine aminotransferase levels were significantly higher in ConA-injected STAP-2 KO mice than in WT mice. Levels of interferon-gamma (IFN-gamma), an important factor for liver necrosis, were also significantly increased in sera of STAP-2 KO mice compared to WT mice after ConA injection. Statistically significant upregulation of Fas ligand (FasL) expression was observed in the livers of ConA-injected STAP-2 KO mice compared to WT mice. In accordance with these results, apoptotic signals were facilitated in STAP-2 KO mice compared to WT mice after ConA injection. Correctively, these results suggest that STAP-2 is involved in the pathogenesis of autoimmune hepatitis by regulating the expression of FasL and the production of IFN-gamma